Voltage-gated sodium (Nav) channels are responsible for the upstroke of the action potential in excitable cells. Nav channels contain tetrameric repeats (i.e., DI to DIV) and each repeat is composed of six transmembrane helices or segments (i.e., segments S1 to S6). The first four segments (S1-S4) comprise a voltage-sensor domain (VSD), in which segment S4 moves in response to a change in membrane potential. Particularly, segment S4 contains an arginine residue that senses the change in membrane potential, and together with the carboxy (C)-terminal half of the segment S3, forms a helix-turn (loop)-helix known as the voltage sensor paddle. The segments S5 and S6 from each tetrameric repeat D1-DIV form a pore domain when the tetrameric repeats D1-DIV are assembled together. Accordingly, the pore domain is opened, closed, and inactivated (i.e., gated) by the movement of the voltage sensor paddle in response to the change in membrane potential.
Humans possess nine highly homologous Nav channel subtypes (i.e., Nav1.1 to Nav1.9), each of which play a distinct role in various tissues, for example, neurons and myocytes to affect nerve and cardiac excitability, respectively. Dysregulation of Nav channel subtypes leads to numerous diseases including cardiac arrhythmia, epilepsy, ataxia, periodic paralysis, and pain disorder. Nav channels are the targets of various drugs, for example, anti-convulsants, local anesthetics, anti-arrhythmics, and analgesics. These drugs often bind an open-inactivated state of the Nav channel. These drugs, however, exhibit poor selectivity among the nine Nav channel subtypes, and thus, non-selective targeting of multiple Nav channel subtypes can lead to off-target effects, which in turn, lead to severe side effects (e.g., cardiac toxicity).
Accordingly, a need exists for the identification and development of new molecules that are selective for one Nav channel subtype over the other eight Nav channel subtypes. Such selectively would allow for the treatment of disease associated with a Nav channel subtype and the prevention of off-target effects that lead to unwanted and serious side effects.